In autoimmune diabetes of rodents beta-cells compensate normally for increased insulin demands. The progressive loss of glucose-stimulated insulin secretion prior to autoimmune diabetes in both rodents and humans must therefore be entirely secondary to an external autoimmune assault upon the glucose-sensing-response system of beta-cells rather than to an intrinsic defect of beta-cells. To determine if antibodies to the most distal exoplasmic component of the system, the glucose transporter, are present at the onset of type 1 diabetes we will survey the ability of IgG from new-onset type 1 diabetic patients to inhibit glucose transport in isolated rat islets and to react with a 55Kd protein in rat hepatocyte membrane preps. These studies may help to identify a beta-cell antigen involved in the pathogenesis of autoimmune diabetes. In contrast to autoimmune diabetes, nonautoimmune diabetes is believed to result from a failure of beta-cells to compensate for antecedent insulin resistance. Here intrinsic defects in the glucose-sensing-signaling-response apparatus are suspected. We propose to use male fa/fa rats as a model of adequate beta-cell compensation for insulin resistance (they do not become diabetic) and male ZDF rats as a model of beta-cell failure to compensate for insulin resistance (they do become diabetic). At 20-40 day intervals throughout the prediabetic period, and when NIDDM supervenes, we will examine insulin and amylin secretory responses of pancreata to glucose and arginine perfusion, the expression of insulin and amylin genes and type of glucose transporter and hexokinase (as important components of the glucose-sensing limb) in compensated and uncompensated models in an attempt to localize an intrinsic defect. The studies should bracket the locus or loci of defects in the AK-cell glucose response system that may play a role in the pathogenesis of types 1 and 2 diabetes.